Depressive disorders are common illnesses that affect more than 18.8 million Americans. “Depression,” National Institute of Mental Health, Publication No. 00-3561 (2000). Depressive disorders, as with other illnesses, come in different forms. Three of the more common depressive disorders include major depression, dysthymia, and bipolar disorder. Major depression is manifested by a combination of symptoms that interfere with a person's ability to function normally, including the ability to work, study, or sleep. Such disabling episodes of depression may occur only, once but more commonly occur several times in a person's lifetime. Dysthymia, a less severe type of depression, involves long term chronic symptoms that do not disable a person but keep a patient from functioning well or feeling good. Bipolar disorder is a form of depression that is characterized by cycling mood changes.
Significant portions of patients treated for depressive disorders do not respond to therapies presently available (i.e., electroconvulsive therapy (ECT), psychotherapy, and orally delivered antidepressant medications, or various combinations of all three therapies). This shortcoming exists despite the introduction of a variety of new more specific and significantly safer medications to the market place (e.g., Prozac®, Zoloft®, Paxil®). Approximately 20–30% of patients treated for depression with antidepressant medications fall into the category of being treatment-resistant. Janicak, P. G. and Martis, B. (1998), “Strategies for Treatment-Resistant Depression,” Clinical Cornerstone 1:58–71; Shelton, R. C. (1999), “Treatment Options for Refractory Depression,” J Clin. Psychiatry 60:57–63; Joffe, R. T. (1997), “Refractory Depression: Treatment Strategies, with Particular Reference to the Thyroid Axis,” J. Psychiatry Neurosci. 22:327–331. Moreover, 30% to 50% of patients do not respond to their initial medication regardless of which class of drug is chosen. The treatment-resistant population consists of patients who have been treated unsuccessfully with multiple drug trials using different classes of orally administered antidepressants, psychotherapy, and potentially ECT.
Similar to depressive disorders, anxiety disorders affect approximately 19 million American adults. “Anxiety Disorders,” National Institute of Mental Health, Publication No. 00-3879 (2000). Anxiety disorders are serious medical illnesses that afflict people's lives with overwhelming anxiety and fear. There are many different anxiety disorders that include panic disorder, obsessive-compulsive disorder, social phobia, and generalized anxiety disorder. Though each of these forms of anxiety disorders may have its own distinct features, they all involve an excessive, irrational fear and/or dread.
Similar to results for the treatment of depressive disorders, a significant portion of patients treated for anxiety disorders do not respond to therapies presently available (i.e., electroconvulsive therapy (ECT), psychotherapy, and orally delivered antidepressant medications, or various combinations of all three). This shortcoming exists despite the introduction of a variety of new more specific and significantly safer medications to the market place.
ECT
A method of treatment for patients who have failed to respond to several classes of therapeutics is ECT. Unfortunately, ECT also has a failure rate of approximately 30–40%. Walter, G., Rey, J. M., and Mitchell, P. B. (1999), “Practitioner Review: Electroconvulsive Therapy in Adolescents,” J Child Psychiatr 40: 325–334. ECT is a therapy that has been steadily increasing in use despite the stigma associated with its historical misuse in psychiatric medicine. ECT is now generally accepted by the American Psychiatric Association and the National Institute of Mental Health as being a safe and effective therapy for major depression. The side effects associated with ECT are generally mild and include headache, myalgia, nausea, memory problems, and confusion. Walter, G., Rey, J. M., and Mitchell, P. B. (1999), “Practitioner Review: Electroconvulsive Therapy in Adolescents,” J Child Psychiatr 40: 325–334. Unfortunately, a small percentage of the ECT-treated patients experience significant cognitive impairments (pre- and/or post treatment memory deficits of durations of weeks to months), manic switching, and tachycardia such that treatment most be discontinued. In addition, ECT requires general anesthesia and a typical course of 8–12 treatments (each treatment takes approximately 15 minutes) administered bi- or tri-weekly. Perhaps the most discouraging aspect of ECT is that greater than half of the successfully treated ECT patients will relapse into clinical depression in less than a year. Sackeim, H. A., Prudic, J., Devanand, D. P., Decina, P., and Malitz, S. (1990), “The Impact of Medication Resistance and Continuation Pharmacotherapy on Relapse Following Response to Electroconvulsive Therapy in Major Depression,” J Clin Psychopharmacol 10: 96–104.
Psychotherapy
Psychotherapy involves talking with a trained mental health professional, such as a psychiatrist. These therapies help a patient gain insight into and resolve their problems through verbal exchange with their psychiatrist. One of the short-term therapies effective in treating both depressive disorders and anxiety disorders is the cognitive-behavioral therapy. Treatments tend to be more successful for mild and moderate forms of depressive and anxiety disorders and usually require medication or ECT treatment along with, or preceding, psychotherapy for the best outcome.
Psychoactive Drugs
The same drugs most commonly used to manage depressive disorders are used to treat anxiety disorders. There are several types of antidepressant medications used to treat depressive and anxiety disorders. Most of the oral antidepressive medications used today are designed to increase the levels of specific monoamine neurotransmitters in the brain (e.g., norepinephrine, serotonin, and dopamine). More recent pharmacologic strategies have focused on antagonizing the effects of specific peptidergic neurotransmitters in the brain, namely corticotropin-releasing hormone and substance P.
Thyrotropin Releasing Hormone
Thyrotropin-releasing hormone (TRH) is a hypothalamic tripeptide hormone which stimulates the pituitary gland to secrete thyroid-stimulating hormone. In addition, TRH functions as a neurotransmitter and neuromodulator in many areas of the central nervous system. TRH (also called protirelin) is a drug that has been studied in the past for the treatment of depression but was shown to produce unpredictable responses when administered parenterally (IV or SQ). Itil, T. M., Patterson, C. D., Polvan, N., Bigelow, A. and Bergey, B. (1975), “Clinical and CNS Effects of Oral and IV Thyrotropin-Releasing Hormone in Depressed Patients,” Dis Nerv Sys 2: 529–536; Prange, A. J., Wilson, I. C., Lara, P. D., Alltop, L. B. and Breese, G. R. (1972), “Effects of Thyrotropin-Releasing Hormone in Depression,” Lancet 2:999–1002. Because TRH is a tripeptide that is subject to proteolysis in the upper gastrointestinal tract, it cannot be administered orally.
TRH has been administered directly to the CNS for the treatment of a psychiatric disease. Callahan, A. M., Frye, M. A., Marangell, L. B., George, M. S., Ketter, T. A., L'Herrou, T. A. and Post, R. M., (1997), “Comparative Antidepressant Effects of Intravenous and Intrathecal Thyrotropin-Releasing Hormone: Confounding Effects of Tolerance and Implications for Therapeutics,” Biol. Psychiatry 41: 264–272; Marangell, L. B., George, M. S., Callahan, A. M., Ketter, T. A., Pazzaglia, P. J., L'Herrou, T. A., Leverich, G. S. and Post, R. M., (1997), “Effects of Intrathecal Thyrotropin-Releasing Hormone (Protirelin) in Refractory Depressed Patients,” Arch. Gen. Psychiatry 54: 214–222. This treatment, a single intrathecal bolus of TRH, was successfully used to treat refractory depression in 7 out of 10 patients. With the exception of sleep deprivation, this is the only therapy that has been demonstrated to produce a rapid (<24 hr) and dramatic improvement in the symptoms of severe depression. However, the study did not involve varying the dosage of the therapeutic substance.
Serotonin Agonists
In the case of serotonergic agonists, direct CNS delivery would be of benefit because many of them only poorly penetrate the blood-brain barrier.
A serotonin agonist, sumatriptan, although not used to treat depression has been used in research studies related to depression and other psychiatric diseases. Stem et al., describes the chronic use of parenteral sumatriptan to treat patients with refractory obsessive-compulsive disorder (OCD). Stem, L., Zohar, J., Cohen, R., and Sasson, Y., (1998), “Treatment of Severe, Drug Resistant Obsessive Compulsive Disorder with the 5HT1D agonist Sumatriptan,” Eur Neuropsychopharmacol 8: 325–328. Although these patients experienced only modest reductions in their OCD behaviors, they demonstrated significant improvements in their symptoms of depression as measured by the Hamilton scale. Because sumatriptan does not readily penetrate the blood-brain barrier, intrathecal delivery would be expected to significantly increase the efficacy of this agent. Saxena, P. R., (1992), “Migraine Therapy and 5-HT Receptor Activity,” J Neurol 238: S36–S37. Arranz et al, reported on reduced 5HT1D receptor density and binding affinity in brain tissues of suicide victims. Arranz, B., Erikson, A., Mellerup, E., Plenge, P. and Marcusson, J., (1994), “Brain 5HT1A, 5HT1D and 5HT2 Receptors in Suicide Victims,” Biol Psychiatry 35:457–463.
Although serotonin (5-HT) is not available as a pharmaceutical agent, certain receptor subtype selective agonists are (e.g., sumatriptan, Imitrex® manufactured by Glaxo Wellcome, 5-HT1 receptor selective agonist currently formulated for injection, 12 mg/ml in saline with no preservatives, indicated use: migraines). The 5-HT1A-receptor has been implicated as a major receptor involved in the antidepressive response to SSRIs. Deakin, J. F. W., (1998), “5HT1A Receptors, Depression, and Anxiety,” Pharmacol Biochem Behav 29: 819–830.
Buspirone, an anxiolytic drug, produces at least part of its effect by activation of 5-HT1A receptors. Sussman, N., (1994), “The Potential Benefits of Serotonin Receptor-Specific Agents,” J Clin Psychiatry 55: 45–51. Mirtazapine, a newly FDA-approved antidepressant (AD), blocks two types of serotonin receptors (5-HT2 and 5-HT3,). Feighner, J. P., (1999), “Mechanism of Action of Antidepressant Medications,” J Clin Psychiatry 60: 4–13. Trazodone is another antidepressant that acts to inhibit neuronal reuptake of serotonin and also antagonizes 5-HT2 receptors. Ruoff, G. E., (1996), “Depression in the Patient with Chronic Pain,” J Fam Pract 43: S25–S34.
Nefazodone, a newer AD, inhibits both 5-HT2 and 5-HT3 receptors. These antidepressive mechanisms suggest that activation of 5-HT2 and 5-HT3 receptors are not involved in the same biochemical pathways associated with selective serotonin reuptake inhibitor (SSRI)-induced efficacy and lends further support to the intrathecal use of sumatriptan (i.e., serotonin-like efficacy without the side effects). The antidepressive effects of SSRIs appears to involve 5-HT1 receptors (1A, 1B, and 1D); insomnia and sexual dysfunction effects have been attributed to 5-HT2 receptor activation and GI side effects have been attributed to 5-HT3 receptor activation. Thase, M. E., Frazer, A., Gorman, J. M., Hirschfeld, R. M. and Roose, S. P., (2000), “Pharmacotherapy of Depression: New Strategies,” A Symposium of the American Psychiatric Association 2000 Annual Meeting. 
Adrenergic Agonists
The majority of antidepressants presently used are designed to affect two major neurotransmitter systems of the brain, norepinephrine and serotonin. Antidepressants inhibit the neuronal reuptake (tricyclic antidepressants—norepinephrine (NE) and 5-HT, SSRIs—just 5-HT, selective norepinephrine reuptake inhibitors—just NE) or degradation (monoamine oxidase inhibitors) of one or both of these neurotransmitters. Although this is the common “first step” pharmacologic effect of antidepressants that leads to a corresponding increase in synaptic neurotransmitter concentrations, the precise biochemical pathways which lead to the ultimate therapeutic outcome have yet to be elucidated. It also is not appreciated why this pharmacologic first step occurs almost immediately after the medication is taken, whereas the patient does not experience relief from his/her symptoms of depression for weeks afterwards.
Intrathecal administration of NE has been studied in animal models of analgesia, spinal cord injury, and motor reflexes. Howe, J. and Yaksh, T. L., (1982), “Changes in Sensitivity to Intrathecal Norepinephrine and Serotonin after 6-Hydroxydopamine, 5,6-Dihydroxytryptamine or Repeated Monoamine Administration,” J Pharmacol Exp Ther 220:311–321; Milne, B., Cervenko, F., Jhamandas, K., Loomis, C. and Sutak, M., (1985), “Analgesic and Tolerance to Intrathecal Morphine and Norepinephrine Infusion via Implanted Mini-Osmotic Pumps in the Rat,” Pain 22: 165–172; Minor, B. G., Persson, M. L., Post, C., Jonsson, G. and Archer, T. (1988), “Intrathecal Noradrenaline Restores 5-Methoxy-N,N-demthyltryptamine Induced Antinociception Abolished by Intrathecal 6-Hydroxydopamine,” J Neural Transm 72: 107–120; Brustein, E. and Rossignol, S. (1999), “Recovery of Locomotion After Ventral and Ventrolateral Spinal Lesions in the Cat: Effects of Noradrenergic and Serotoninergic Drugs,” J Neurophysiol 81: 1513–1530; Wiesenfield-Hallin, Z., (1987), “Intrathecal Noradrenaline has a Dose-Dependent Inhibitory or Facilitory Effect on the Flexion Reflex in the Rat,” Acta Physiol Scand 130: 507–511. In these studies, no undesirable or unpredicted responses were attributed to intrathecal NE administration.
Recent theories proposed on the biochemical mechanisms of ADs focus on adrenoceptors and the enzyme responsible for NE synthesis, tyrosine hydroxylase. Leonard, B. E., (1997), “Noradrenaline in Basic Models of Depression,” Eur Neuropsychopharmacol 7: 511–516. Many ADs produce a decrease in function and/or adrenoceptor density as well as decreases in the tyrosine hydroxylase levels in the brain. Thase, M. E., Frazer, A., Gorman, J. M., Hirschfeld, R. M. and Roose, S. P., (2000), “Pharmacotherapy of Depression: New Strategies,” A Symposium of the American Psychiatric Association 2000 Annual Meeting. These are biochemical endpoints which may be accomplished more effectively by direct NE infusion.
The direct infusion of NE as opposed to relying on oral ADs to inhibit neuronal NE uptake may provide several advantages. Both methods result in increasing the amount of extracellular NE, but traditional ADs are limited by the endogenous pool of NE available in the vesicles of the nerve terminals. By providing an exogenous source of the transmitter, the concentration of NE may be increased above the endogenous limit. Those skilled in the art will realize that in pharmacology drugs that exert their effects indirectly (i.e., are dependent on the causing the release of or inhibiting the degradation of a primary endogenous molecule) are usually limited in the maximum effect they can produce. This efficacy limitation is a direct result of the limited pool of endogenous agonist. It is also conceivable that the lack of an adequate clinical response to oral reuptake inhibitors in select patient populations is a result of depleted or inaccessible pools of NE within the terminals of the presynaptic neurons. It is reasonable to assume that only with an intact endogenous supply of presynaptic NE can the initial pharmacologic impact of reuptake inhibition be expected to occur. An exogenous supply of NE would be able to circumvent this “theoretical” problem. Using exogenous NE may potentially speed recovery and provide efficacy in patients who have previously been shown to be resistant to oral therapy.
Corticotropin-Releasing Factor Antagonists
Corticotropin-releasing factor (CRF) is an endogenous 41-amino-acid peptide that is produced in the brain and which is critical for mediating responses to stress. It is released by the hypothalamus and serves to activate the pituitary and adrenal glands resulting in the release of epinephrine and cortisol into the blood. It is know in the art of psychiatry that patients with depression have elevated plasma cortisol levels as a result of an overactive hypthalamic-pituitary-adrenal (HPA) axis. It is also appreciated that stress, especially prolonged stress and early-childhood stress, can induce depression. Since CRF is the initial chemical mediator of the stress response, drugs which block the effect of CRF may block this stress cascade and be useful in treating depression and anxiety disorders. Published scientific literature supports this but a successful therapeutic that works by blocking this pathway has yet to make into the clinic.
Companies are pursuing agents which can be administered orally similar to all the other drugs which are currently marketed for depression. A general type of CRF antagonist that can block the relevant receptors but that cannot be given orally or cross the blood-brain barrier are peptide antagonists. Although peptide antagonists are often used in research and function quite effectively to block the targeted receptor, because they would be digested in the gastrointestinal tract if given orally and not cross the blood-brain barrier to reach their site of action if given IV or SQ, these peptidergic agents have not been been pursued as viable therapeutic candidates.
Substance P Antagonists
Substance P is an 11-amino-acid endogenous peptide neurotransmitter that is known to be involved in the transmission of pain information to the central nervous system. Substance P produces its effects by activating cell-surface receptors known as neurokinin-1 (NK-1) receptors. Recently, it has been appreciated both in animal studies and clinical trials that substance P places an important role in mediating stress responses and that antagonism of the NK-1 receptors may have positive effects in treating mood and anxiety disorders. Kramer, M. S., (1998), “Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors,” Science Volume 281 September 11, 1640–1625. Substance P concentrations are especially high in the brain structure known as the amygdala, an important area that regulates mood and anxiety.